Fukushima J. Med. Sci., Vol. 61, No. 2, 2015
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[Original Article]
OUTCOME OF CLIVAL CHORDOMAS AFTER SKULL BASE SURGERIES WITH MEAN FOLLOW-UP OF 10 YEARS TAKAMITSU TAMURA1,2), TAKU SATO1), YUGO KISHIDA1), MASAHIRO ICHIKAWA1), KEIKO ODA1), EIJI ITO3), TADASHI WATANABE4), JUN SAKUMA1) and KIYOSHI SAITO1) 1)
Department of Neurosurgery, Fukushima Medical University, Fukushima, Japan, 2)Department of Neurosurgery Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan, 3)Department of Neurosurgery, Gifu Prefectural Tajimi Hospital, Tajimi, Japan, 4)Department of Neurosurgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan (Received April 9, 2015, accepted July 24, 2015) Abstract : Background and Objective : Skull base chordomas are clinically malignant because of the difficulty of total removal, high recurrence rate, and occasional drop metastasis. Although aggressive surgical resection and postoperative radiation have been recommended, the long-term outcome remains unsatisfactory. Methods : From 1992 to 2011, we treated 24 patients with skull base chordoma using aggressive surgical removal as a principal strategy. Skull base approaches were selected according to tumor extension to remove the tumor and surrounding bone as completely as possible. After surgery, all patients were closely observed with MRI to find small and localized recurrent tumors, which were treated with gamma-knife radiosurgery or surgical resection. The mean postoperative follow-up duration was 10.2 years (range, 1-17.2 years). Results : The 5-, 10-, and 15-year overall survival rates were 86%, 72%, and 72%, respectively. The 5- and 10-year progression-free survival rates were 47% and 35%, respectively. Tumor extension to the brainstem and partial tumor removal were the factors related to poor survival. Conclusions : Our results suggest that aggressive surgical removal improves the long-term outcome of patients with skull base chordoma. We would like to emphasize that skull base chordomas should be aggressively removed using various skull base approaches. Key words : clival chordoma, skull base surgery, long-term outcome
INTRODUCTION
Chordoma is a rare tumor, presumably originating from remnants of the primitive notochord. The incidence of chordomas ranges from 0.8 to 5 cases per million individuals per year. Approximately 50% of chordomas develop in the sacrococcygeal region, 35% in the spheno-occipital region, and 15% in the vertebrae. Skull base chordomas arise in and around the upper and middle clivus as well as the spheno-occipital synchondrosis. Although they are considered to be slowly growing low-grade malignancies, their behavior is more aggressive because of infiltration to local bone, extension to adjacent
soft tissue, high recurrence rate, and occasional metastasis1). Clival chordomas are difficult to treat because of their deep location and the invasive nature of the tumor. An aggressive surgical approach to attempt radical resection and subsequent postoperative radiation therapy is recommended as the current therapeutic algorithm1 3). The degree of tumor resection has proved to be an independent factor for tumor recurrence and the strongest determinant of survival1). Long-term follow-up reports have shown that longer survival rates were correlated with more extensive tumor removal2 6). In our previous study, we demonstrated long-
Corresponding author : Kiyoshi Saito E-mail : [email protected] https://www.jstage.jst.go.jp/browse/fms http://www.fmu.ac.jp/home/lib/F-igaku/
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term control of clival chordoma with initial aggressive surgical resection, and gamma knife stereotactic radiosurgery (SRS) for recurrence7). The mean follow-up after surgical resection at that time was 7.3 years. In the present study, we show further longterm outcome with the mean follow-up of 10.2 years and evaluate clinical factors for poor outcome.
approaches. The surrounding bone was removed or drilled out as completely as possible, and the clival dura was thoroughly cleaned up. The location and extension of the tumors with surgical approaches are shown in Table 1. Selected approaches were a transsphenoidal approach : microscopic (2 patients) before 1998 and endoscopic (6 patients) thereafter, an anterior craniofacial approach with preserving olfaction (7 patients) 8) , staged lateral suboccipital and anterior craniofacial approaches (1 patient), an orbitozygomatic or zygomatic approach (2 patients), an anterior or combined petrosal approach (3 patients), 3-staged surgery : right and left transcondylar approaches and anterior approach, either transoral or mandibular swing approach (2 patients), and a combined zygomatic and extended endonasal endoscopic approach (1 patient). If a dural defect had been made by the tumor itself or was made by surgical procedures, it was patched
PATIENTS AND METHODS
From 1992 to 2011, we treated 24 consecutive patients with clival chordoma in Nagoya University Hospital, Fukushima Medical University Hospital, and their affiliated hospitals : 15 men and 9 women, age ranging from 7 to 75 years old (mean, 46) (Table 1). Two patients had recurrent tumor after surgery or multiple surgeries and radiation. Our principal strategy is aggressive surgical resection. We tried total removal of the tumors using various skull base
Table 1. Clinical factors, tumor location and extension, and selected approach of 24 patients with clival chordomas Age Gender Male Female Primary/recurrent Primary Recurrent Tumor location (approach) Mainly clivus with intradural extension Anterior extension to Sphenoid sinus with intradural extension Anterior cranial base Lateral extension to Petrous apex Cavernous sinus, petrous apex Cavernous sinus, retropharynx Inferior extension to Axis, retropharynx Posterior extension with intradural extension Pure intradural Dural defect Negative Positive Intradural tumor extension Extension to the brainstem Adhesion to the brainstem Invasion in the brainstem
7-75 (mean, 46) 15 9 22 2 6 (transsphenoidal) 2 (transsphenoidal) 4 (anterior craniofacial) 1 (lateral suboccipital/anterior craniofacial) 2 (anterior craniofacial) 1 (anterior craniofacial) 2 (orbitozygomatic, zygomatic) 1 (zygomatic+endonasal endoscopic) 2 (3-staged) 2 (combined petrosal) 1 (anterior petrosal) 16 8 6 1 3
LONG-TERM OUTCOME OF CLIVAL CHORDOMAS
using fascial graft and covered with either a nasoseptal flap or a temporoparietal galeal flap9,10). After surgery, all patients were closely observed with magnetic resonance imaging (MRI) every 4-6 months. Our secondary strategy is to find recurrent tumors as early as possible, and treat them by surgical resection or SRS. Since the recurrent tumors were usually small and localized after aggressive resection, they could be treated with high-dose radiation (marginal dose ≥ 16 Gy, whenever possible) using SRS. Some tumors that adhered to the brainstem or recurred in the spine were treated with fractionated stereotactic radiotherapy (SRT, Novalis). The mean duration of postoperative follow-up was 10.2 years (range, 1-17.2 years). Statistical analysis of data was performed using SPSS. Overall survival and progression-free survival (PFS) were calculated using Kaplan - Meier analysis. To detect clinical factors affecting survival, a log-rank test as well as uni- and multivariate analyses using the Cox proportional hazards model were performed. Values of p55 at the initial treatment (p=0.034), in those without intradural tumor extension than those with (p=0.044), in those without tumor extension into the brainstem than those with (p=0.001, Fig. 2a), and in those with total or subtotal removal than those with partial removal (p=0.016, Fig. 2b). Univariate analysis revealed correlations between tumor extension to the brainstem or the degree of tumor resection and the overall survival (Table 3). In multivariate analysis, significant relation with the overall survival was found in the tumor extension to the brainstem (p=0.021) but not in the degree of tumor resection (p=0.160). The relationships between the PFS and clinical
Table 3. Correlation between the clinical factors and overall survival based on the univariate analysis of Cox proportional hazards modeling. Clinical factors Gender Male vs. female Age at initial treatment > 55 year old vs. ≤ 55 year old Without vs. with dural defect Without vs. with intradural tumor extension Without vs. with tumor extension to brainstem Degree of tumor resection Total or subtotal vs. partial Without vs. with tumor recurrence
Hazard ratio (95% CI)
p
2.549 (0.284-22.831)
0.403
7.630 (0.842-69.111) 4.343 (0.713-26.441) 5.223 (0.868-31.418) 11.837 (1.932-72.520)
0.071 0.111 0.071 0.008
6.669 (1.111-40.048) 2.195 (0.242-19.903)
0.038
3.255 (0.336-31.578)
0.309
0.485
MIB-1 labeling index < 3.44% vs. > 3.44%
LONG-TERM OUTCOME OF CLIVAL CHORDOMAS
a
a
b
b
Fig. 2. Kaplan-Meier curves for overall survival of 24 patients with clival chordoma. a : Survival of patients without tumor extension to the brainstem (n=20) was significantly better than that of patients with such extension (n=4) by log-rank test (p=0.001). b : Survival of patients with total or subtotal tumor removal (n=22) was significantly better than that of patients with partial tumor removal (n=2) by log-rank test (p=0.016).
factors were analyzed. Kaplan - Meier log - rank analysis indicated that PFS was significantly longer in patients without tumor extension into the brainstem than those with (p=0.019, Fig. 3a), in those with total or subtotal removal than those with partial removal (p=0.015, Fig. 3b), and in those with MIB-1 index of the tumor < 3.44% than those with ≥ 3.44% (p=0.019). Univariate analysis revealed correlations between tumor extension to the brainstem, the degree of tumor resection, or MIB-1 index and the PFS (Table 4). In multivariate analysis, however, correlations between these factors and the PFS were not significant.
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Fig. 3. Kaplan-Meier curves for progressionfree survival of 24 patients with clival chordoma. a : Progression-free survival of patients without tumor extension to the brainstem (n=20) was significantly better than that of patients with such extension ( n = 4 ) b y l o g - r a n k t e s t ( p = 0 . 0 1 9 ) . b : Progression - free survival of patients with total or subtotal tumor removal (n=22) was significantly better than that of patients with partial tumor removal (n=2) by logrank test (p=0.015).
ILLUSTRATIVE CASES
Case 1 An 18-year-old woman was referred to us with diplopia due to left abducens nerve palsy. MRI revealed a clival tumor extended posteriorly with severe compression of the brainstem (Fig. 4a, b). We selected a right combined petrosal approach. Through a dural defect, the tumor extended into the intradural space without adhesion to or invasion into the brainstem. The tumor was totally removed (Fig. 4c, d). After surgery, the patient suffered from bilateral abducens nerve and left oculomotor nerve palsy. During a follow-up period of 10 years and 10 months, these symptoms were resolved and
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Table 4. Correlation between the clinical factors and progression-free survival based on the univariate analysis of Cox proportional hazards modeling. Clinical factors Gender Male vs. female Age at initial treatment > 55 year old vs. ≤ 55 year old Without vs. with dural defect Without vs. with intradural tumor extension Without vs. with tumor extension to brainstem Degree of tumor resection Total or subtotal vs. partial
Hazard ratio (95% CI)
p
2.255 (0.681-7.467)
0.183
1.292 (0.414-4.032) 0.615 (0.168-2.246) 1.051 (0.288-3.835) 4.560 (1.130-18.391)
0.659 0.462 0.940 0.033
6.299 (1.142-34.747)
0.035
4.075 (1.162-14.292)
0.028
MIB-1 labeling index < 3.44% vs. ≥ 3.44%
Fig. 4. Case 1. a, b : Preoperative axial T1-weighted (a) and sagittal enhanced (b) MRI showing a clival tumor extended posteriorly and severely compressing the brainstem. The tumor occupied the right and left Meckel’s caves (arrows). c, d : Postoperative enhanced axial (c) and sagittal (d) MRI showing total removal of the tumor.
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Fig. 5. Case 2. a, b : Preoperative enhanced axial MRI showing a clival tumor extending to the left cavernous sinus and petrous bone. c : Postoperative CT showing resected clival and petrous bone. d, e : T2-weighted (d) and enhanced (e) axial MRI 29 months after surgery showing a recurrent tumor at the right posterior clinoid process (arrows).
no recurrence was observed. Case 2 A 25-year-old woman was referred to us with symptoms of left facial dysesthesia and spasm. MRI revealed a clival tumor extended laterally into the cavernous sinus and the petrous bone (Fig. 5 a, b). We selected an orbitozygomatic approach. The tumor was totally removed. The petrous bone was removed to expose the entire petrous carotid artery, eustachian tube and part of the cochlea. The clivus was thoroughly drilled until to reach the normal bone at the remnant lower clivus (Fig. 5c). The skull base defect was reconstructed using a temporoparietal galeal flap. After surgery, the patient temporarily suffered from facial numbness and abducens nerve palsy. Twenty-nine months after surgery, MRI revealed a recurrent tumor in the right side of the posterior clinoid process (Fig. 5d, e), which was treated by SRS. For 10 years and 11 months after the initial surgery, the recurrent tumor was kept under control and no other recurrence was found. Case 3 A 55-year-old man was referred to us with diplopia due to left abducens nerve palsy. MRI re-
vealed a clival tumor extended to the sphenoid sinus (Fig. 6a, b). We selected an anterior craniofacial approach. The tumor was totally removed (Fig. 6c). After surgery, the diplopia improved. Thirteen months after surgery, a recurrence was found in the left cavernous sinus and treated by SRS. Then, almost every year, a new recurrence was found in the ethmoid sinus, cavernous sinus, medial part of the orbit, or cranial base (Fig. 6d). In total, 7 recurrent tumors were treated by SRS and controlled for 7 years and 5 months after the initial surgery (Fig. 6e). DISCUSSION
Prognosis of chordoma patients remains unsatisfactory with 5-year overall survival rates of around 60-80%11 16). In the USA, the analysis of 400 patients from 1973 to1995 revealed 5- and 10-year relative survival rates of 67.5% and 39.9%, respectively 13). In the UK, registry data showed that the 5-year survival rate of patients who were diagnosed between 1998 and 2002 was 56%15). A systematic review of 560 non-duplicated patients demonstrated 5- and 10-year survival rates of 63% and 16%, respectively12). Radical surgical resection has been shown to be a key factor for longer survival 2,3,6). -
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Fig. 6. Case 3. a, b : Preoperative enhanced coronal (a) and axial (b) MRI showing a clival tumor extending to the sphenoid sinus. c : Postoperative sagittal T1-weighted MRI showing total removal of the tumor. d : T2weighted axial MRI 53 months after surgery showing a recurrent tumor (arrows), which was treated by the fourth gamma knife radiosurgery. e : T2-weighted MRI 89 months after surgery showing controlled recurrent tumors (arrows).
Previously, we reported the follow-up results of 19 patients7) : all were alive at the end of the study with mean follow-up of 7.3 years. Since some patients died after the publication of that paper, we reviewed the follow-up data again with newly treated patients and longer follow-up outcome. Our mean postoperative follow-up of 10.2 years was significantly long in order to evaluate the long-term outcome. The 5- and 10-year overall survival rates of our patients, 86% and 72%, respectively, proved that aggressive removal of chordomas improves longterm outcome of chordoma. We selected various skull base approaches and showed that aggressive removal is a fundamental factor for better outcome. Recently, an extended endonasal endoscopic approach has been developed17 19). Koutourousiou M, et al. reported results of the endoscopic endonasal approach on 60 patients with a mean follow-up of 17.8 months18). The limitations for gross total resection, achieved in two thirds of their patients, were tumor volume greater than 20 ml, tumor location in the lower clivus with lateral extension, and previously treated disease. The complications included CSF leak (20%) resulting in meningitis (3.3%), and carotid injuries occurred in 2 patients. Even in endoscopic surgeries, -
total tumor resection with removal or drilling of the surrounding bone should be performed. Longer follow-up results are necessary to confirm the real benefits of the extended endonasal endoscopic approach. Besides incomplete surgical resection, clinical factors such as old age, female sex, large tumor size, prior surgery and prior radiotherapy have been associated with poor prognosis20 23). Wu Z, et al. analyzed 79 of 106 consecutive patients with an average follow-up of 63.9 months16). The history of radiotherapy or surgery, dedifferentiated pathology, and insufficient tumor resection were risk factors for long-term survival and recurrence. In our previous paper, we demonstrated that higher MIB-1 labeling index was associated with shorter progression-free survival7). In the data of this paper, tumor adhesion or invasion to the brainstem was a factor of poor long-term outcome. High dose radiation is another important factor for better control of the chordoma1,3). Proton-beam therapy has been used to deliver high dose radiation to clival chordomas24,25). Data have shown an increase in local control and survival with the use of proton therapy26). Recently, carbon ion radiation therapy has been available27,28). Uhl M, et al. treat-
LONG-TERM OUTCOME OF CLIVAL CHORDOMAS
ed 155 patients with 5-year and 10-year local control rates of 72% and 54%, respectively, and 5-year and 10-year overall survival rates of 85% and 75%, respectively29). Fractionated stereotactic radiation therapy is another method for high dose radiation. Jiang B, et al. reported the outcome of 20 chordoma patients with a mean marginal dose of 32.5 Gy (1850 Gy). The overall survival at 5 years was 52.5%30). Bugoci DM, et al. reported 12 patients who underwent surgical resection followed by high-dose fractionated stereotactic radiotherapy. The overall 5-year survival rate in that study was 76.4%31). We selected SRS for recurrent tumors32,33) and treated them with high dose radiation since they had been localized and small after total or subtotal removal by initial aggressive surgery. Koga T, et al. showed that sufficient marginal doses of SRS at least 16 Gy appeared crucial34). Kano H, et al. reported results of SRS from the North American Gamma Knife Consortium 35). In their paper, the 5 - year overall survival rate was 80% for the entire group and 93% for the no prior fractionated radiation group. Marginal dose of ≥ 15 Gy and smaller tumor volume were significantly associated with better tumor control32,35). They concluded that SRS was a potent treatment option for small chordomas, especially in younger patients and as part of multipronged attack that includes surgical resection.
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CONCLUSION
We report long-term outcome (mean follow-up of 10.2 years) of 24 patients with skull base chordoma treated using aggressive surgical removal as a principal strategy. Skull base approaches were selected according to tumor extension to remove the tumor and surrounding bone as completely as possible. The 5-, 10-, and 15-year overall survival rates were 86%, 72%, and 72%, respectively. The 5- and 10-year progression-free survival rates were 47% and 35%, respectively. Our results clearly suggest that aggressive surgical removal improves the longterm outcome of patients with skull base chordoma.
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14. CONFLICT OF INTEREST
We have no relationship with companies that may have a financial interest. REFERENCES
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[Original Article]
OUTCOME OF CLIVAL CHORDOMAS AFTER SKULL BASE SURGERIES WITH MEAN FOLLOW-UP OF 10 YEARS TAKAMITSU TAMURA1,2), TAKU SATO1), YUGO KISHIDA1), MASAHIRO ICHIKAWA1), KEIKO ODA1), EIJI ITO3), TADASHI WATANABE4), JUN SAKUMA1) and KIYOSHI SAITO1) 1)
Department of Neurosurgery, Fukushima Medical University, Fukushima, Japan, 2)Department of Neurosurgery Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan, 3)Department of Neurosurgery, Gifu Prefectural Tajimi Hospital, Tajimi, Japan, 4)Department of Neurosurgery, Nagoya Daini Red Cross Hospital, Nagoya, Japan (Received April 9, 2015, accepted July 24, 2015) Abstract : Background and Objective : Skull base chordomas are clinically malignant because of the difficulty of total removal, high recurrence rate, and occasional drop metastasis. Although aggressive surgical resection and postoperative radiation have been recommended, the long-term outcome remains unsatisfactory. Methods : From 1992 to 2011, we treated 24 patients with skull base chordoma using aggressive surgical removal as a principal strategy. Skull base approaches were selected according to tumor extension to remove the tumor and surrounding bone as completely as possible. After surgery, all patients were closely observed with MRI to find small and localized recurrent tumors, which were treated with gamma-knife radiosurgery or surgical resection. The mean postoperative follow-up duration was 10.2 years (range, 1-17.2 years). Results : The 5-, 10-, and 15-year overall survival rates were 86%, 72%, and 72%, respectively. The 5- and 10-year progression-free survival rates were 47% and 35%, respectively. Tumor extension to the brainstem and partial tumor removal were the factors related to poor survival. Conclusions : Our results suggest that aggressive surgical removal improves the long-term outcome of patients with skull base chordoma. We would like to emphasize that skull base chordomas should be aggressively removed using various skull base approaches. Key words : clival chordoma, skull base surgery, long-term outcome
INTRODUCTION
Chordoma is a rare tumor, presumably originating from remnants of the primitive notochord. The incidence of chordomas ranges from 0.8 to 5 cases per million individuals per year. Approximately 50% of chordomas develop in the sacrococcygeal region, 35% in the spheno-occipital region, and 15% in the vertebrae. Skull base chordomas arise in and around the upper and middle clivus as well as the spheno-occipital synchondrosis. Although they are considered to be slowly growing low-grade malignancies, their behavior is more aggressive because of infiltration to local bone, extension to adjacent
soft tissue, high recurrence rate, and occasional metastasis1). Clival chordomas are difficult to treat because of their deep location and the invasive nature of the tumor. An aggressive surgical approach to attempt radical resection and subsequent postoperative radiation therapy is recommended as the current therapeutic algorithm1 3). The degree of tumor resection has proved to be an independent factor for tumor recurrence and the strongest determinant of survival1). Long-term follow-up reports have shown that longer survival rates were correlated with more extensive tumor removal2 6). In our previous study, we demonstrated long-
Corresponding author : Kiyoshi Saito E-mail : [email protected] https://www.jstage.jst.go.jp/browse/fms http://www.fmu.ac.jp/home/lib/F-igaku/
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term control of clival chordoma with initial aggressive surgical resection, and gamma knife stereotactic radiosurgery (SRS) for recurrence7). The mean follow-up after surgical resection at that time was 7.3 years. In the present study, we show further longterm outcome with the mean follow-up of 10.2 years and evaluate clinical factors for poor outcome.
approaches. The surrounding bone was removed or drilled out as completely as possible, and the clival dura was thoroughly cleaned up. The location and extension of the tumors with surgical approaches are shown in Table 1. Selected approaches were a transsphenoidal approach : microscopic (2 patients) before 1998 and endoscopic (6 patients) thereafter, an anterior craniofacial approach with preserving olfaction (7 patients) 8) , staged lateral suboccipital and anterior craniofacial approaches (1 patient), an orbitozygomatic or zygomatic approach (2 patients), an anterior or combined petrosal approach (3 patients), 3-staged surgery : right and left transcondylar approaches and anterior approach, either transoral or mandibular swing approach (2 patients), and a combined zygomatic and extended endonasal endoscopic approach (1 patient). If a dural defect had been made by the tumor itself or was made by surgical procedures, it was patched
PATIENTS AND METHODS
From 1992 to 2011, we treated 24 consecutive patients with clival chordoma in Nagoya University Hospital, Fukushima Medical University Hospital, and their affiliated hospitals : 15 men and 9 women, age ranging from 7 to 75 years old (mean, 46) (Table 1). Two patients had recurrent tumor after surgery or multiple surgeries and radiation. Our principal strategy is aggressive surgical resection. We tried total removal of the tumors using various skull base
Table 1. Clinical factors, tumor location and extension, and selected approach of 24 patients with clival chordomas Age Gender Male Female Primary/recurrent Primary Recurrent Tumor location (approach) Mainly clivus with intradural extension Anterior extension to Sphenoid sinus with intradural extension Anterior cranial base Lateral extension to Petrous apex Cavernous sinus, petrous apex Cavernous sinus, retropharynx Inferior extension to Axis, retropharynx Posterior extension with intradural extension Pure intradural Dural defect Negative Positive Intradural tumor extension Extension to the brainstem Adhesion to the brainstem Invasion in the brainstem
7-75 (mean, 46) 15 9 22 2 6 (transsphenoidal) 2 (transsphenoidal) 4 (anterior craniofacial) 1 (lateral suboccipital/anterior craniofacial) 2 (anterior craniofacial) 1 (anterior craniofacial) 2 (orbitozygomatic, zygomatic) 1 (zygomatic+endonasal endoscopic) 2 (3-staged) 2 (combined petrosal) 1 (anterior petrosal) 16 8 6 1 3
LONG-TERM OUTCOME OF CLIVAL CHORDOMAS
using fascial graft and covered with either a nasoseptal flap or a temporoparietal galeal flap9,10). After surgery, all patients were closely observed with magnetic resonance imaging (MRI) every 4-6 months. Our secondary strategy is to find recurrent tumors as early as possible, and treat them by surgical resection or SRS. Since the recurrent tumors were usually small and localized after aggressive resection, they could be treated with high-dose radiation (marginal dose ≥ 16 Gy, whenever possible) using SRS. Some tumors that adhered to the brainstem or recurred in the spine were treated with fractionated stereotactic radiotherapy (SRT, Novalis). The mean duration of postoperative follow-up was 10.2 years (range, 1-17.2 years). Statistical analysis of data was performed using SPSS. Overall survival and progression-free survival (PFS) were calculated using Kaplan - Meier analysis. To detect clinical factors affecting survival, a log-rank test as well as uni- and multivariate analyses using the Cox proportional hazards model were performed. Values of p55 at the initial treatment (p=0.034), in those without intradural tumor extension than those with (p=0.044), in those without tumor extension into the brainstem than those with (p=0.001, Fig. 2a), and in those with total or subtotal removal than those with partial removal (p=0.016, Fig. 2b). Univariate analysis revealed correlations between tumor extension to the brainstem or the degree of tumor resection and the overall survival (Table 3). In multivariate analysis, significant relation with the overall survival was found in the tumor extension to the brainstem (p=0.021) but not in the degree of tumor resection (p=0.160). The relationships between the PFS and clinical
Table 3. Correlation between the clinical factors and overall survival based on the univariate analysis of Cox proportional hazards modeling. Clinical factors Gender Male vs. female Age at initial treatment > 55 year old vs. ≤ 55 year old Without vs. with dural defect Without vs. with intradural tumor extension Without vs. with tumor extension to brainstem Degree of tumor resection Total or subtotal vs. partial Without vs. with tumor recurrence
Hazard ratio (95% CI)
p
2.549 (0.284-22.831)
0.403
7.630 (0.842-69.111) 4.343 (0.713-26.441) 5.223 (0.868-31.418) 11.837 (1.932-72.520)
0.071 0.111 0.071 0.008
6.669 (1.111-40.048) 2.195 (0.242-19.903)
0.038
3.255 (0.336-31.578)
0.309
0.485
MIB-1 labeling index < 3.44% vs. > 3.44%
LONG-TERM OUTCOME OF CLIVAL CHORDOMAS
a
a
b
b
Fig. 2. Kaplan-Meier curves for overall survival of 24 patients with clival chordoma. a : Survival of patients without tumor extension to the brainstem (n=20) was significantly better than that of patients with such extension (n=4) by log-rank test (p=0.001). b : Survival of patients with total or subtotal tumor removal (n=22) was significantly better than that of patients with partial tumor removal (n=2) by log-rank test (p=0.016).
factors were analyzed. Kaplan - Meier log - rank analysis indicated that PFS was significantly longer in patients without tumor extension into the brainstem than those with (p=0.019, Fig. 3a), in those with total or subtotal removal than those with partial removal (p=0.015, Fig. 3b), and in those with MIB-1 index of the tumor < 3.44% than those with ≥ 3.44% (p=0.019). Univariate analysis revealed correlations between tumor extension to the brainstem, the degree of tumor resection, or MIB-1 index and the PFS (Table 4). In multivariate analysis, however, correlations between these factors and the PFS were not significant.
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Fig. 3. Kaplan-Meier curves for progressionfree survival of 24 patients with clival chordoma. a : Progression-free survival of patients without tumor extension to the brainstem (n=20) was significantly better than that of patients with such extension ( n = 4 ) b y l o g - r a n k t e s t ( p = 0 . 0 1 9 ) . b : Progression - free survival of patients with total or subtotal tumor removal (n=22) was significantly better than that of patients with partial tumor removal (n=2) by logrank test (p=0.015).
ILLUSTRATIVE CASES
Case 1 An 18-year-old woman was referred to us with diplopia due to left abducens nerve palsy. MRI revealed a clival tumor extended posteriorly with severe compression of the brainstem (Fig. 4a, b). We selected a right combined petrosal approach. Through a dural defect, the tumor extended into the intradural space without adhesion to or invasion into the brainstem. The tumor was totally removed (Fig. 4c, d). After surgery, the patient suffered from bilateral abducens nerve and left oculomotor nerve palsy. During a follow-up period of 10 years and 10 months, these symptoms were resolved and
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Table 4. Correlation between the clinical factors and progression-free survival based on the univariate analysis of Cox proportional hazards modeling. Clinical factors Gender Male vs. female Age at initial treatment > 55 year old vs. ≤ 55 year old Without vs. with dural defect Without vs. with intradural tumor extension Without vs. with tumor extension to brainstem Degree of tumor resection Total or subtotal vs. partial
Hazard ratio (95% CI)
p
2.255 (0.681-7.467)
0.183
1.292 (0.414-4.032) 0.615 (0.168-2.246) 1.051 (0.288-3.835) 4.560 (1.130-18.391)
0.659 0.462 0.940 0.033
6.299 (1.142-34.747)
0.035
4.075 (1.162-14.292)
0.028
MIB-1 labeling index < 3.44% vs. ≥ 3.44%
Fig. 4. Case 1. a, b : Preoperative axial T1-weighted (a) and sagittal enhanced (b) MRI showing a clival tumor extended posteriorly and severely compressing the brainstem. The tumor occupied the right and left Meckel’s caves (arrows). c, d : Postoperative enhanced axial (c) and sagittal (d) MRI showing total removal of the tumor.
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Fig. 5. Case 2. a, b : Preoperative enhanced axial MRI showing a clival tumor extending to the left cavernous sinus and petrous bone. c : Postoperative CT showing resected clival and petrous bone. d, e : T2-weighted (d) and enhanced (e) axial MRI 29 months after surgery showing a recurrent tumor at the right posterior clinoid process (arrows).
no recurrence was observed. Case 2 A 25-year-old woman was referred to us with symptoms of left facial dysesthesia and spasm. MRI revealed a clival tumor extended laterally into the cavernous sinus and the petrous bone (Fig. 5 a, b). We selected an orbitozygomatic approach. The tumor was totally removed. The petrous bone was removed to expose the entire petrous carotid artery, eustachian tube and part of the cochlea. The clivus was thoroughly drilled until to reach the normal bone at the remnant lower clivus (Fig. 5c). The skull base defect was reconstructed using a temporoparietal galeal flap. After surgery, the patient temporarily suffered from facial numbness and abducens nerve palsy. Twenty-nine months after surgery, MRI revealed a recurrent tumor in the right side of the posterior clinoid process (Fig. 5d, e), which was treated by SRS. For 10 years and 11 months after the initial surgery, the recurrent tumor was kept under control and no other recurrence was found. Case 3 A 55-year-old man was referred to us with diplopia due to left abducens nerve palsy. MRI re-
vealed a clival tumor extended to the sphenoid sinus (Fig. 6a, b). We selected an anterior craniofacial approach. The tumor was totally removed (Fig. 6c). After surgery, the diplopia improved. Thirteen months after surgery, a recurrence was found in the left cavernous sinus and treated by SRS. Then, almost every year, a new recurrence was found in the ethmoid sinus, cavernous sinus, medial part of the orbit, or cranial base (Fig. 6d). In total, 7 recurrent tumors were treated by SRS and controlled for 7 years and 5 months after the initial surgery (Fig. 6e). DISCUSSION
Prognosis of chordoma patients remains unsatisfactory with 5-year overall survival rates of around 60-80%11 16). In the USA, the analysis of 400 patients from 1973 to1995 revealed 5- and 10-year relative survival rates of 67.5% and 39.9%, respectively 13). In the UK, registry data showed that the 5-year survival rate of patients who were diagnosed between 1998 and 2002 was 56%15). A systematic review of 560 non-duplicated patients demonstrated 5- and 10-year survival rates of 63% and 16%, respectively12). Radical surgical resection has been shown to be a key factor for longer survival 2,3,6). -
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Fig. 6. Case 3. a, b : Preoperative enhanced coronal (a) and axial (b) MRI showing a clival tumor extending to the sphenoid sinus. c : Postoperative sagittal T1-weighted MRI showing total removal of the tumor. d : T2weighted axial MRI 53 months after surgery showing a recurrent tumor (arrows), which was treated by the fourth gamma knife radiosurgery. e : T2-weighted MRI 89 months after surgery showing controlled recurrent tumors (arrows).
Previously, we reported the follow-up results of 19 patients7) : all were alive at the end of the study with mean follow-up of 7.3 years. Since some patients died after the publication of that paper, we reviewed the follow-up data again with newly treated patients and longer follow-up outcome. Our mean postoperative follow-up of 10.2 years was significantly long in order to evaluate the long-term outcome. The 5- and 10-year overall survival rates of our patients, 86% and 72%, respectively, proved that aggressive removal of chordomas improves longterm outcome of chordoma. We selected various skull base approaches and showed that aggressive removal is a fundamental factor for better outcome. Recently, an extended endonasal endoscopic approach has been developed17 19). Koutourousiou M, et al. reported results of the endoscopic endonasal approach on 60 patients with a mean follow-up of 17.8 months18). The limitations for gross total resection, achieved in two thirds of their patients, were tumor volume greater than 20 ml, tumor location in the lower clivus with lateral extension, and previously treated disease. The complications included CSF leak (20%) resulting in meningitis (3.3%), and carotid injuries occurred in 2 patients. Even in endoscopic surgeries, -
total tumor resection with removal or drilling of the surrounding bone should be performed. Longer follow-up results are necessary to confirm the real benefits of the extended endonasal endoscopic approach. Besides incomplete surgical resection, clinical factors such as old age, female sex, large tumor size, prior surgery and prior radiotherapy have been associated with poor prognosis20 23). Wu Z, et al. analyzed 79 of 106 consecutive patients with an average follow-up of 63.9 months16). The history of radiotherapy or surgery, dedifferentiated pathology, and insufficient tumor resection were risk factors for long-term survival and recurrence. In our previous paper, we demonstrated that higher MIB-1 labeling index was associated with shorter progression-free survival7). In the data of this paper, tumor adhesion or invasion to the brainstem was a factor of poor long-term outcome. High dose radiation is another important factor for better control of the chordoma1,3). Proton-beam therapy has been used to deliver high dose radiation to clival chordomas24,25). Data have shown an increase in local control and survival with the use of proton therapy26). Recently, carbon ion radiation therapy has been available27,28). Uhl M, et al. treat-
LONG-TERM OUTCOME OF CLIVAL CHORDOMAS
ed 155 patients with 5-year and 10-year local control rates of 72% and 54%, respectively, and 5-year and 10-year overall survival rates of 85% and 75%, respectively29). Fractionated stereotactic radiation therapy is another method for high dose radiation. Jiang B, et al. reported the outcome of 20 chordoma patients with a mean marginal dose of 32.5 Gy (1850 Gy). The overall survival at 5 years was 52.5%30). Bugoci DM, et al. reported 12 patients who underwent surgical resection followed by high-dose fractionated stereotactic radiotherapy. The overall 5-year survival rate in that study was 76.4%31). We selected SRS for recurrent tumors32,33) and treated them with high dose radiation since they had been localized and small after total or subtotal removal by initial aggressive surgery. Koga T, et al. showed that sufficient marginal doses of SRS at least 16 Gy appeared crucial34). Kano H, et al. reported results of SRS from the North American Gamma Knife Consortium 35). In their paper, the 5 - year overall survival rate was 80% for the entire group and 93% for the no prior fractionated radiation group. Marginal dose of ≥ 15 Gy and smaller tumor volume were significantly associated with better tumor control32,35). They concluded that SRS was a potent treatment option for small chordomas, especially in younger patients and as part of multipronged attack that includes surgical resection.
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CONCLUSION
We report long-term outcome (mean follow-up of 10.2 years) of 24 patients with skull base chordoma treated using aggressive surgical removal as a principal strategy. Skull base approaches were selected according to tumor extension to remove the tumor and surrounding bone as completely as possible. The 5-, 10-, and 15-year overall survival rates were 86%, 72%, and 72%, respectively. The 5- and 10-year progression-free survival rates were 47% and 35%, respectively. Our results clearly suggest that aggressive surgical removal improves the longterm outcome of patients with skull base chordoma.
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14. CONFLICT OF INTEREST
We have no relationship with companies that may have a financial interest. REFERENCES
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